Circadian rhythms have recently become recognized as modulators of a wide array of physiological and pathological processes, including glucose homeostasis, exercise endurance, blood pressure and tumorigenesis. The long-term goal of the candidate is to develop novel therapeutic approaches for metabolic disease by continuing to investigate the interrelationship between circadian rhythms and cellular and organismal metabolism. An underlying hypothesis of this proposal is that metabolic physiology can be modulated at the transcriptional level by nutrient-sensing circadian repressors regulating nuclear hormone receptor (NR) function; advancing our functional understanding of these receptor and repressor interactions may highlight new therapeutic strategies for treating metabolic disease. The circadian clock components cryptochromes (Cry1 and Cry2) are nutrient-responsive transcriptional regulators by virtue of their susceptibility to phosphorylation by AMP-activated protein kinase (AMPK), which causes their proteasomal degradation. Preliminary studies indicate that cryptochromes interact with and repress several nuclear hormone receptors, making them novel nutrient-responsive nuclear receptor corepressors. Nuclear hormone receptors are widely studied as critical regulators of several aspects of metabolic physiology. Biochemical, genetic, molecular and physiological approaches will be used to uncover the roles of Cry1 and Cry2 in nuclear hormone receptor pathways governing the control of glucose homeostasis and exercise physiology, in the following specific aims: Aim I, characterize the roles of Cry1 and Cry2 in nuclear hormone receptor-dependent transcription (analysis of the physical and functional associations between Cry1 and Cry2 and mammalian nuclear hormone receptors); Aim 2, examine the roles of Cry1 and Cry2 in glucose homeostasis (characterization of glucose regulation in Cry-deficient mice before and after hormone treatment; examination of hormone-dependent gene regulation in livers); Aim 3, examine the roles of Cry1 and Cry2 in exercise physiology (characterize muscle biology, physiology and exercise endurance in Cry-deficient mice; examine gene expression in muscles before and after pharmacological treatments).